Project 1 of the Myanmar Regional ICEMR addresses questions in Research Areas A, Epidemiology and B, Transmission. Malaria elimination may require eradicating all parasites from all infected persons, not just those with clinical symptoms. If clinical malaria represents the ?tip of the iceberg?, understanding the rest of the iceberg?whether it poses risk or even benefit to infected individuals, and how it contributes to transmission in different epidemiological settings?will be important for malaria control and elimination. Using an ultrasensitive reverse transcription PCR (usPCR) assay, we are finding highly heterogeneous malaria prevalence of malaria in Myanmar. The World Health Organization recently endorsed mass drug administration (MDA) in Southeast Asia, and MDA is being undertaken in Myanmar based on subclinical malaria prevalence as measured by usPCR. However, no previous studies have assessed the clinical risks or transmission potential of the extremely low density malaria infections detected by these tests. The first aim of Project 1 is to measure the dynamics of subclinical malaria infections and assess their contribution to the risk of clinical malaria and to transmission potential in Southeast Asia. We hypothesize that persistent subclinical Plasmodium falciparum and P. vivax infections represent chronic infection that protects against clinical manifestations of malaria, and that subclinical malaria infections represent a potential source of transmission. A multicenter, matched cohort study will be conducted at six sites in Myanmar and along its borders with China and Bangladesh. usPCR will be used to measure the prevalence and dynamics of subclinical ultralow density P. falciparum and P. vivax infection. The association of subclinical infection with incidence of clinical malaria and infectivity will be estimated using multivariate and time-to-event models. This aim will generate evidence to guide recommendations about MDA and other elimination interventions. We also designed and are using protein and peptide microarrays to measure antibody responses to large numbers of variants of diverse malaria and mosquito proteins. These microarrays may prove useful as surveillance tools to measure exposure to parasites and mosquitoes, and provide a way to characterize genetic diversity in low density infections that are difficult to genotype. The second aim is to estimate recent and remote exposure to malaria parasites and vectors in humans using these arrays to measure seroreactivity to diverse malaria and mosquito antigens, testing the hypotheses that antibody responses to diverse variants of P. falciparum and P. vivax antigens are associated with exposure to new malaria infections; antibody responses to diverse Anopheles antigens are independently associated with risk factors for mosquito exposure and with local vector diversity and abundance; and seroreactivity to gametocyte proteins is associated with infectivity. This aim will generate sets of informative proteins and/or peptides useful for surveillance tools to guide elimination interventions, with potential for further development as a point-of-care sero-surveillance test to help malaria elimination programs stratify malaria risk.